A major goal expressed by NIAID and other agencies charged with development of the U.S. biodefense research strategy is a broad spectrum activity that mitigates catastrophic biothreats across a wide spectrum of agents. Such therapeutic activities have been difficult to identify and require new understanding and paradigms of the immune system or the pathogens. The novel discovery that reduced expression of CD45, a protein associated with immune cells, profoundly modulates the immune response capability in a manner that protects the host against a variety of lethal pathogens provides opportunities for novel therapeutic interventions that target the host immune system to achieve the goal of a broad spectrum activity. The approach is based on findings using a series of mice genetically modified to express reduced levels of CD45. Reduced CD45 expression was shown to provide survival protection from three Category A (B. anthracis, Ebola virus and Marburg virus) and one Category C (influenza) biodefense pathogens. Since these four pathogens represent highly diverse infectious organisms and pathologies, it is likely that the reduction of CD45 will also provide therapeutic benefit against additional pathogens. Thus, the significance of the proposed studies is not only the potential for pathogen protection from a biodefense standpoint but also for pandemic disease control. The reduction of CD45 expression to enhance immune protection against biodefense pathogens represents a new and unexpected property of CD45 and a novel approach for immunotherapy. Since permanent, genetically-reduced CD45 expression, as occurs when only one functional gene copy is present, produces no detectable adverse effects in mouse or human, a therapeutic that induces transient reduction of CD45 function is very likely to have an excellent safety profile, particularly if only CD45 is targeted. One approach to such selective targeting is to utilze CD45-specific genetic sequences. CD45-specific siRNA will be delivered using a unique lipid-polymer hybrid nanoparticle platform to achieve selective CD45 reduction. This feasibility study will test and advance this technology, initially using cultured cells followed by evaluation of CD45 reduction and modulation of immune function in mice.